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Dihydropyridine compounds for treating or preventing metabolic disorders

a technology of dihydropyridine and metabolic disorders, applied in the field of substituted dihydropyridine compounds, can solve the problems of dangerously high circulating glucose levels, inability to completely produce insulin, and insufficient production of insulin, so as to improve blood glucose levels, improve blood lipid levels, and reduce blood glucose levels

Inactive Publication Date: 2005-09-15
SYNTA PHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0022] In another embodiment, the compounds of the invention are 3-substituted-dihydropyridine compounds or 4-substituted-1,4,5,6,7,8-hexahydroquinoline compounds characterized by an ability to reduce elevated blood glucose levels without significant acute toxicity.
[0030] In another embodiment, the invention provides a method of achieving two or more of the following: (i) reducing blood glucose levels, (ii) improving blood lipid levels, (iii) improving blood insulin levels, and (iv) improving insulin sensitivity, said method comprising administering to a subject in need thereof an effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof or a pharmaceutical composition comprising an effective amount of a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1, or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. In accordance with these embodiments, a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1 may be administered in combination with other therapies (e.g., prophylactic or therapeutic agents).

Problems solved by technology

Diabetics, however, produce too little insulin, entirely cease producing insulin or progressively become resistant to the action of insulin.
As a result, circulating levels of glucose remain dangerously high and in some cases, blood levels of insulin and lipids are also abnormal.
These individuals tend to have high levels of circulating lipids (including cholesterol), which contributes to development of vascular complications.
Furthermore, diabetes is the leading cause of new cases of blindness, with approximately 5000 new cases occurring annually.

Method used

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  • Dihydropyridine compounds for treating or preventing metabolic disorders
  • Dihydropyridine compounds for treating or preventing metabolic disorders
  • Dihydropyridine compounds for treating or preventing metabolic disorders

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of 2-(2-azido-ethoxymethyl)-4-(2-chloro-phenyl)-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxylic acid ethyl ester

[0655] A. 4-(2-azido-ethoxy)-3-oxo-butyric acid ethyl ester

[0656] A solution of 2-azidoethanol (8.7 g, 100 mmol) in THF (20 ml) was added to a suspension of sodium hydride (8.8 g, 220 mmol, 60% dispersion in oil) in THF (150 ml). The mixture was stirred at room temperature for 1 h and then cooled to 0-5° C. Ethyl-4-chloroacetoacetate (16.5 g, 100 mmol) in THF (20 ml) was then added dropwise over a period of 0.5 h. The mixture was stirred at room temperature for additional 16 h and diluted with EtOAc (100 ml) and the pH was adjusted to 6-7 with 2 N HCL. Sufficient water was added to dissolve the solid, and the organic layer was then separated. The aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated. The product was purified by column chromatography on si...

example 2

Synthesis of 2-(2-amino-ethoxymethyl)-4-(2-chloro-phenyl)-7,7-dimethyl-5-oxo-1,4,5,6,7,8-Hexahydro-quinoline-3-carboxylic acid ethyl ester

[0659] Compound 1 can be prepared by Route A or Route B, each set forth below.

[0660] A mixture of 2-(2-azido-ethoxymethyl)-4-(2-chloro-phenyl)-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl ester (2.12 g, 4.6 mmol) and tin (II) chloride (2.18 g, 11.5 mmol) in CH2Cl2 / MeOH (2:1, 12 ml) containing 2 drops of water was stirred at room temperature for about 6 h. The reaction mixture was diluted with CH2Cl2 (100 ml) and a saturated solution of NaHCO3 was added to adjust the pH to 9-10, and the layers were then separated. The aqueous layer was further extracted with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and evaporated. The product was purified by column chromatography on silica gel (CH2Cl2:MeOH, 95:5) to give 2-(2-amino-ethoxymethyl)-(2-chloro-phenyl)-7,7-dimethyl-5-oxo-1,4,5,6,7,8-hexahydro-q...

example 3

Synthesis of 2-(2-amino-ethoxymethyl)-7,7-dimethyl-5-oxo-4-pyridin-2-yl-1,4,5,6,7,8-hexahydro-quinoline-3-carboxylic acid ethyl ester

[0666]

[0667] A solution of 2-azidoethanol (8.7 g, 100 mmol) in THF (20 ml) was added to suspension of sodium hydride (8.8 g, 220 mmol, 60% dispersion in oil) in THF (150 ml). The mixture was stirred at room temperature for about 1 h and then cooled to 0-5° C. Ethyl-4-chloroacetoacetate (16.5 g, 100 mmol) in THF (20 ml) was then added drop wise over a period of about 0.5 h. The mixture was stirred at room temperature for about 16 h and diluted with EtOAc (100 ml) and the pH was adjusted to 6-7 with 2 N HCl. Sufficient water was added to dissolve the solid, and the layers were then separated. The aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4, filtered and evaporated. The product was purified by column chromatography on silica gel (Hexane-EtOAc, 95:5) to give 4-(2-azido-ethoxy)-3-ox...

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Abstract

This invention relates to dihydropyridine compounds of formula (I): or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof wherein A2, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, and m are defined herein, and compositions comprising such compounds. The invention also relates to methods of preventing or treating metabolic disorders, such as diabetes mellitus, and conditions and complications associated with diabetes mellitus, comprising administering to a subject in need thereof a compound of formula (1) or a composition comprising such a compound. The invention further relates to kits comprising a compound of formula (I).

Description

RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 60 / 502,353, filed on Sep. 10, 2003 and U.S. Provisional Application No. 60 / 561,264, filed on Apr. 9, 2004. The entire teaching of the above referenced provisional applications are incorporated herein by reference.FIELD OF THE INVENTION [0002] The present invention relates to substituted dihydropyridine compounds and compositions comprising substituted dihydropyridine compounds. The invention further relates to methods for preventing or treating metabolic disorders, such as diabetes mellitus, and conditions and complications associated with diabetes mellitus, comprising administering to a subject in need thereof a substituted dihydropyridine compound, or a composition comprising such a compound. The invention still further relates to kits comprising a substituted dihydropyridine compound. BACKGROUND OF THE INVENTION [0003] Metabolic disorders are conditions characterized by defective m...

Claims

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Application Information

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IPC IPC(8): A61K31/47A61K31/4741A61K31/4743A61K31/4745C07D215/54C07D221/20C07D401/04C07D401/12C07D401/14C07D405/04C07D471/02C07D491/02C07D491/04C07D498/02
CPCC04B35/632C07D215/54C07D221/20C07D401/04C07D401/12C07D401/14C07D405/04C07D491/04A61P3/00A61P3/06A61P3/10
Inventor ONO, MITSUNORIWADA, YUMIKOSUN, LIJUNCHEN, SHOUJUNPRZEWLOKA, TERESAZHANG, SHIJIEBORELLA, CHRISTOPHERKOYA, KEIZOFOLEY, KEVINXIA, ZHI-QIANGLI, HAOZHOU, DAN
Owner SYNTA PHARMA CORP
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